Down regulation of Lyn Src family kinases in these AML cells by siRNA o

Both receptor and non receptor protein tyrosine kinases are essential enzymes in many cellular signaling pro cesses regulating cell growth, differentiation, apoptosis, migration, immune responses, adhesion and metabolism, Members of the Src family of tyrosine kinases are signaling intermediates that can control aspects of these and other biological processes, Lyn is a member of the Src purchase abt263 family of intracellular membrane associated tyrosine kinases Each member has a unique N terminal region encoding a myristoylation site, and may contain one or two palmitoylation sites, followed by hom ologous domains for protein interaction, as well as a kinase domain, Lyn has two splice variants that result in the gener ation of p53 and p56 kDa protein isoforms, designated as LynA and LynB, which differ by a 20 amino acid region in the SH4 domain that encompasses a pY motif, The reversible N terminal lipid modification and isoform specific pY32 motif potentially complicate understanding Lyns func tion through their latent ability to regulate activity, inter actions, and subcellular localization.<br><br> As with other Src family kinases Lyn is regulated by protein interactions through its SH2 SH3 domains as well as via phosphoryl ation status, In its inactive state supplier Adriamycin Lyn is phosphorylated at its carboxyl terminus by C terminal Src kinase creating a binding site for its own SH2 domain. Lyns SH3 domain can bind an intramolecular proline motif situated between the SH2 and kinase domains, helping generate a stabilized in active kinase confirmation.<br><br> Activation of Lyn involves dephosphorylation of the C terminal tyrosine by phosphatases such as CD45 and SHP 2, as well as through interactions with SH2 and or SH3 domain binding motifs, which compete with Lyns own SH3 SH2 intramolecular interaction sites, thus releasing the auto inhibitory オーダー ABT-199 configuration of the kinase domain. Lyn can then trans autophosphorylate within the activation loop to generate a highly active enzyme. Phosphoryl ation of this loop alters its structure such that the Mg ATP pocket becomes more accessible, thus increasing kinase activity potential, The structure of Lyns kin ase domain has been solved in an active but unpho sphorylated apo form as well as in complex with several inhibitors, revealing the molecular basis for its inhibition by these drugs, In vitro analysis indicates that the Y397 phosphorylation status potentiates the greatest ac tivity regulation, however, in vivo, this may be substantially modulated by the C terminal motif and or SH2 SH3 domain interactions.<br><br> Indeed, the activation in activation regulatory cycle of Lyn is further controlled by its association with different scaffold adaptors that are restricted to different subcellular compartments, such as Cbp PAG1, which predominantly resides within lipid rafts, In the inactivation cycle of Lyn, phos phatases such as SHP 1 and SHP 2, which are them selves attracted to molecules phosphorylated by Lyn, are known to dephosphorylate the pY397 activation loop site, and are thus important in down regulating this emzyme, The involvement of Src family kinases including Lyn in various signaling cascades is gradually being eluci dated, While Lyn was originally identi fied as a hematopoietic specific kinase it is expressed in many tissues and is involved in the transmission of sig nals from a number of receptors such as B cell receptor, GM CSF receptor, FcER1, Epo receptor, and c kit, among others, as well as integrins, Lyn phosphorylates a number of signaling molecules, including the immu noreceptor tyrosine based inhibitory activation motifs on PIR B SIRP and FcR, as well as PI 3 kinase, FAK, ras GAP, PLC1 2, HS1, Cbp PAG1, STAT5 and MAP kinase.<br><br>